1. Field of the Invention
This invention relates to novel 4-oxo-naphthyridine- and 4-oxo-quinoline-3-carboxylic acids derivatives having anti-bacterial activity, to compositions containing the same, and to novel amines and intermediates used in the preparation of the same.
2. Description of the Prior Art
R. Albrecht, Progress in Drug Research, 21, 9-104(1977), describes the development of numerous structural variants having antibacterial activity which are based on the structure of nalidixic acid (1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid) having the following structural formula: ##STR1##
One such variant described by Albrecht is the class of compounds referred to as quinoline derivatives, more particularly, derivatives of 1,4-dihydro-4-oxo-3-quinolinecarboxylic acids having the following structural formula: ##STR2##
Such quinolones unsubstituted in the benzene nucleus, B, wherein R is H, are described as having only slight antibacterial activity. There are disclosed numerous quinoline derivatives having the above structural formula wherein the benzene nucleus, B, possesses substituents selected from halogen, alkyl, cycloalkyl, unsubstituted and substituted phenyl and pyridyl, piperidinyl and piperazinyl to name but a few, especially when such substituent is in the 7-position. See pages 12-15.
Further, there are disclosed numerous quinoline derivatives having the above structural formula wherein the pyridone nucleus, A, possesses various substituents in the 1-position selected from unsubstituted lower alkyl groups or lower alkyl substituted with, for example, halogen and hydroxy-groups, lower alkenyl, alkynyl, and unsubstituted and substituted phenyl. Particularly, it is disclosed that in a comparison of activity of these quinoline derivatives having an alkyl group in the 1-position, the effects achieved with smaller radicals always proved to be best and, further, that as a rule the best activity is obtained with the ethyl group. See page 25, lines 1-5.
Another variant described by Albrecht is the class of compounds referred to as naphthyridine derivatives, i.e. 1,8-naphthyridine or more particularly 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid derivatives, having the following structural formula: ##STR3## Among the 1,8-naphthyridine derivatives having the above structural formula, there are disclosed derivatives having piperazinyl and pyrrolidinyl groups in the 7-position and ethyl in the 1-position. See pages 51-56. As regards substituents in the 1-position, it is disclosed that among those same 1-position substituents described above in the quinoline derivatives, maximum activity is achieved with ethyl or propyl groups whereas all smaller or larger alkyl groups or those with additional double bonds or functional groups decrease activity. See page 60, lines 8-19.
M. P. Wentland and J. B. Cornett, Annual Reports In Medicinal Chemistry, 20, 145-154 (1985) describe modifications and developments in the area of quinolone antibacterial agents subsequent to the review of Albrecht above, particularly with emphasis on developments in 6-fluoro-7-piperazinylquinolones directed toward increasing antibacterial activity against Gram-positive bacteria and against anaerobes as well as against Gram-negative bacteria in comparison to the activity demonstrated by nalidixic acid. Among the more recent agents disclosed are the agents referred to as norfloxacin (1-ethyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxo-quinoline-3-carboxyl ic acid) and ciprofloxacin (1-cyclopropyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxo-quinoline-3-ca rboxylic acid).
U.S. Pat. No. 3,590,036 discloses numerous 1-substituted-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids and derivatives thereof having the following formula, including nalidixic acid mentioned above, wherein the substituent on the 1-position can be aliphatic hydrocarbon radicals having one to ten carbon atoms inclusive such as, for example, alkyl, alkenyl and alkynyl radicals. Illustrative of these radicals are methyl, ethyl, n-propyl, i-propyl, 2-butyl, isoamyl, and the like, when alkyl; and 2-propenyl (allyl), 2-methyl-2-propenyl, 3-butenyl, and the like when alkenyl. The substituents on the pyridine nucleus, that is at the 5-, 6-, and 7-positions of the naphthyridine ring system, can be lower-alkyl, halo, and lower-cycloalkylamino. ##STR4## U.S. Pat. No. 4,284,629 discloses the preparation of certain 4-pyridone-3-carboxylic acids and derivatives thereof having the following structural formula: ##STR5## or a salt thereof wherein R.sup.1a denotes an alkyl, cycloalkyl, aralkyl, aryl or an amino group; R.sup.2a denotes a hydrogen atom or an alkyl, aralkyl or an aryl group; R.sup.3a denotes a derivative of a carboxyl group such as a nitrile or ester group; and up to three of the symbols A, B, D and E denote a nitrogen atom and the remaining of the symbols A, B, D, and E denote an optionally substituted carbon atom. Although the patent discloses that particularly preferred aliphatic radicals R.sup.1a are ethyl and tert-butyl, there is disclosed among the thirty-five actual examples a single example illustrating tertiary-butyl as the R.sup.1a radical, namely, 1-t-butyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (Example 25). However, no biological activity data is disclosed for this example.
U.S. Pat. Nos. 4,359,578 and 4,352,803 disclose antibacterial compounds having the following structural formula: ##STR6## wherein X is a halogen atom, especially a fluorine atom, R.sup.1 is an ethyl or vinyl group, and R.sup.2 is a hydrogen atom or a lower alkyl group, and non-toxic salts thereof.
U.S. Pat. No. 4,146,719 discloses the compound, 1-ethyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxoquinoline-3-carboxylic acid (norfloxacin) and the hydrates and addition salts thereof.
German Offen. DE 3142854 discloses 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl-quinoline-3-carboxy lic acids including the specific compound wherein the substituent in the 7-position is unsubstituted piperazinyl (ciprofloxacin) as well as 4-substituted piperazinyl wherein the substituent is methyl, ethyl, or beta-hydroxyethyl.
EP 0,153,163 discloses antibacterial compounds having the following structural formula: ##STR7## wherein X is CH, C--Cl, C--F, C--OH, C--O--alkyl having from one to three carbon atoms, C--NH--alkyl having from one to three carbon atoms or N; Y is H, F, Cl or Br; Z is representative of heterocyclic substituents having the formula ##STR8## wherein R.sup.3 is hydrogen, methyl, ethyl, 1- or 2-propyl; R.sup.1 is hydrogen, alkyl having one to six carbon atoms or a cation; and R.sup.2 is alkyl having one to four carbon atoms, vinyl, haloalkyl, or hydroxyalkyl having two to four carbon atoms, or cycloalkyl having three to six carbon atoms. Among the numerous actual examples there are disclosed the preparation of two compounds wherein R.sup.2 is a tertiary alkyl group, namely, 1-methylcyclopropyl (See Examples 61 and 68). However, no data showing biological activity for these compounds is disclosed.
U.S. Pat. No. 4,571,396 (corresponding to EP 0,159,174) discloses certain naphthyridine- and quinoline-carboxylic acids having antibacterial activity and having the following structural formula: ##STR9## wherein Z is an amine substituent selected from ##STR10## in which R is hydrogen, alkyl of one to three carbon atoms, hydroxyalkyl of two to three carbon atoms, benzyl or p-aminobenzyl; R' is hydrogen or alkanoyl of one to three carbon atoms; X is CH, CF, or N; Y is hydrogen, fluoro, or amino; R.sup.1 is hydrogen, alkyl having from one to six carbon atoms or a cation; and R.sup.2 is alkyl having one to four carbon atoms, vinyl, haloalkyl, or hydroxyalkyl having two to four carbon atoms, or cycloalkyl having three to six carbon atoms, and the pharmaceutically acceptable acid addition or base salts thereof.
U.S. Pat. No. 4,556,658 discloses antibacterial compounds having the following structural formula ##STR11## wherein R.sup.1 and R.sup.2 are identical or different and represent a C.sub.1 -C.sub.4 alkyl radical which is optionally substituted by a hydroxyl, amino, methylamino or dimethylamino group, and R.sup.1 and R.sup.2 together with the nitrogen atom to which they are bonded, furthermore form a 5- or 6-membered heterocyclic ring which can additionally have, as a ring member, the atoms or groups --O--, --S--, --SO--, --SO.sub.2 -- or &gt;NR.sup.3. The patented compounds are said to couple low toxicity with a broad antibacterial spectrum against Gram-positive and Gram-negative bacteria, in particular against Enterobacteriaceae, especially against those which are resistant to various antibiotics such as penicillins, cephalosporins, aminoglycosides, sulfonamides and the like.
U.S. Pat. No. 4,578,473 discloses an improved process to produce a compound having the structural formula ##STR12## wherein A is a substituted amino group, R.sup.1 R.sup.2 N--; X is H or F; and R.sup.2 is C.sub.1 -C.sub.3 alkyl or C.sub.1 -C.sub.6 cycloalkyl.
U.S. Pat. Nos. 4,559,341 and 4,559,342 disclose derivatives of the above-mentioned ciprofloxacin having the structural formula ##STR13##
EP 0 166 939 discloses antibacterial 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-oxo-1-piperazinyl)-3-quinoli necarboxylic acids having the structural formula ##STR14##
EP 0 167 763 discloses antibacterial compounds having the structural formula ##STR15## wherein X.sup.1 and X.sup.2 are the same or different and represent Cl or F provided that they are not both F at the same time and R.sup.1 and R.sup.2, together with the nitrogen atom to which they are bound, form a 5- or 6-membered ring which can further include --O--, --S--, --SO--, --SO.sub.2 --, &gt;N--R.sup.3 or --CONR.sup.3.
Spanish Patent 8504767 discloses a process to produce compounds having the structural formula ##STR16## wherein R.sub.1 is hydrogen or lower alkyl, for example, methyl, ethyl, or isopropyl, and R.sub.2 is methyl or ethyl, by reacting a 3-chloro-4-fluoro-(N-alkyl)aniline with ethoxymethylenemalononitrile, cyclizing the resulting intermediate under Friedel-Crafts conditions, and reacting the resulting intermediate with an appropriate piperazine.
South African Patent Application Publication No. 853954 discloses antibacterial compounds having the structural formula ##STR17##
U.S. Pat. No. 4,563,448 discloses a method of combating plant-pathogenic bacteria using a cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivative of the formula ##STR18##
Great Britain Patent Application Publication 2 160 519 A discloses quinolone compounds having antibacterial activity having the structural formula ##STR19## wherein R.sub.1 is H or alkyl.
EP 0 132 845 discloses antibacterial 1,8-naphthyridine derivatives of the formula ##STR20## wherein R.sub.1, R.sub.2 and R.sub.3 are the same or different and can be hydrogen or lower alkyl having 1 to 5 carbon atoms.
EP 0 134 165 discloses antibacterial 7-(pyrrol-1-yl) derivatives of 1-ethyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and 1-ethyl-1,4-dihydro-4-oxo-(1,8-naphthyridine)-3-carboxylic acid of the formula ##STR21## wherein X is a carbon atom or nitrogen atom and R is hydrogen or fluoro.
U.S. Pat. No. 4,341,784 discloses antibacterial 7-(3-amino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyr idine-3-carboxylic acids of the formula ##STR22##
Although the recently developed compounds exhibit improvements in antibacterial activity, such as a broader activity spectrum, increased potency, improved absorbability, increased duration of action and improved stability, in comparison with previous compounds, there remains a need for compounds having an advantageous combination of these and other desirable properties.
These and other advantages as will be apparent to those skilled in the art to which this invention pertains are acheived by this invention which is described as follows.